The present invention relates to systems and methods for providing a barrier to prevent contact of an optical probe from surrounding features of the environment. More particularly, the present invention relates to systems and methods for providing a disposable sheath for a medical apparatus.
An important requirement exists for an instrument that will provide rapid and automatic diagnostic information, for example of cancerous and otherwise diseased tissue. In particular, there is a need for an instrument that would map the extent and stage of cancerous tissue without having to excise a large number of tissue samples for subsequent biopsies. In the current art, the medical profession relies generally on visual analysis and biopsies to determine specific pathologies and abnormalities. Various forms of biochemical imaging are used as well. Unique optical responses of various pathologies are being exploited in attempts to characterize biological tissue as well. These prior art techniques, however, contain limitations. pathologies are being exploited in attempts to characterize biological tissue as well. These prior art techniques, however, contain limitations.
For example, performing a tissue biopsy and analyzing the extracted tissue in the laboratory requires a great deal of time. In addition, tissue biopsies can only characterize the tissue based upon representative samples taken from the tissue. This results in a large number of resections being routinely performed to gather a selection of tissue capable of accurately representing the sample. In addition, tissue biopsies are subject to sampling and interpretation errors. Magnetic resonance imaging is a successful tool, but is expensive and has serious limitations in detecting pathologies that are very thin or in their early stages of development.
One technique used in the medical field for tissue analysis is induced fluorescence. Laser induced fluorescence utilizes a laser tuned to a particular wavelength to excite tissue and to cause the tissue to fluoresce at a set of secondary wavelengths that can then be analyzed to infer characteristics of the tissue. Fluorescence can originate either from molecules normally found within the tissue, or from molecules that have been introduced into the body to serve as marker molecules.
Although the mechanisms involved in the fluorescence response of biological tissue to UV excitation have not been clearly defined, the fluorescence signature of neoplasia appears to reflect both biochemical and morphological changes. The observed changes in the spectra are similar for many cancers, which suggest similar mechanisms are at work. For example, useful auto-fluorescence spectral markers may reflect biochemical changes in the mitochondria, e.g., in the relative concentration of nicotinamide adenine dinucleotide (NADH) and flavins. Mucosal thickening and changes in capillary profusion are structural effects that have been interpreted as causing some typical changes in the spectroscopic record.
The major molecules in biological tissue which contribute to fluorescence emission under 337 nm near UV light excitation, have been identified as tryptophan (390 nm emission), chromophores in elastin (410 nm) and collagen (300 nm), NADH (470 nm), flavins (520 nm) and melanin (540 nm). However, it should be noted that in tissue, there is some peak shifting and changes in the overall shape relative to the pure compounds. Accordingly, the sample can be illuminated with a UV beam of sufficiently short wavelength and record responses from the above enumerated wavelengths of light in order to determine the presence of each of above identified contributions to tissues types.
It has been further shown that hemoglobin has an absorption peak between 400 and 540 nm, while both oxyhemoglobin and hemoglobin have strong light absorption above 600 nm. Blood distribution may also influence the observed emission spectra of elastin, collagen, NAD, and NADH. Further compounds present in tissue which may absorb emitted light and change the shape of the emitted spectra include myoglobin, porphyrins, and dinucleotide co-enzymes.
A general belief is that neoplasia has high levels of NADH because its metabolic pathway is primarily anaerobic. The inability of cells to elevate their NAD+: NADH ratio at confluence is a characteristic of transformed cells related to their defective growth control. The ratio of NAD+: NADH is an indicator of the metabolic capability of the cell, for example, its capacity for glycolysis versus gluconeogenesis. Surface fluorescence has been used to measure the relative level of NADH in both in vitro and in vivo tissues. Emission spectra obtained from individual myocytes produce residual green fluorescence, probably originating from mitochondrial oxidized flavin proteins, and blue fluorescence is consistent with NADH of a mitochondrial origin.
Collagen, NADH, and flavin adenine dinucleotide are thought to be the major fluorophores in colonic tissue and were used to spectrally decompose the fluorescence spectra. Residuals between the fits and the data resemble the absorption spectra of a mix of oxy-and deoxy-hemoglobin; thus the residuals can be attributed to the presence of blood.
Alfano, U.S. Pat. No. 4,930,516, teaches the use of luminescence to distinguish cancerous from normal tissue when the shape of the visible luminescence spectra from the normal and cancerous tissue are substantially different, and in particular when the cancerous tissue exhibits a shift to the blue with different intensity peaks. For example, Alfano discloses that a distinction between a known healthy tissue and a suspect tissue can be made by comparing the spectra of the suspect tissue with the healthy tissue. According to Alfano, the spectra of the tissue can be generated by exciting the tissue with substantially monochromatic radiation and comparing the fluorescence induced at least at two wavelengths.
Alfano, in U.S. Pat. No. 5,042,494, teaches a technique for distinguishing cancer from normal tissue by identifying how the shape of the visible luminescence spectra from the normal and cancerous tissue are substantially different.
Alfano further teaches, in U.S. Pat. No. 5,131,398, the use of luminescence to distinguish cancer from normal or benign tissue by employing (a) monochromatic or substantially monochromatic excitation wavelengths below about 315 nm, and, in particular, between about 260 and 315 nm, and, specifically, at 300 nm, and (b) comparing the resulting luminescence at two wavelengths about 340 and 440 nm.
Alfano, however, fails to teach a method capable of distinguishing between normal, malignant, benign, tumorous, dysplastic, hyperplastic, inflamed, or infected tissue. Failure to distinguish these entities prevents selecting appropriate therapies. While the simple ratio, difference and comparison analysis of Alfano and others have proven to be useful tools in cancer research and provocative indicators of tissue status, these have not, to date, enabled a method nor provided means which are sufficiently accurate and robust to be clinically acceptable for cancer diagnosis.
It is understood that the actual spectra obtained from biological tissues are extremely complex and thus difficult to resolve by standard peak matching programs, spectral deconvolution or comparative spectral analysis. Furthermore, spectral shifting further complicates such attempts at spectral analysis. Last, laser fluorescence and other optical responses from tissues typically fail to achieve depth resolution because either the optical or the electronic instrumentation commonly used for these techniques entail integrating the signal emitted by the excited tissue over the entire illuminated tissue volume.
Rosenthal, U.S. Pat. No. 4,017,192, describes a technique for automatic detection of abnormalities, including cancer, in multi-cellular bulk biomedical specimens, which purports to overcome the problems associated with complex spectral responses of biological tissues. Rosenthal teaches the determination of optical responses (transmission or reflection) data from biological tissue over a large number of wavelengths for numerous samples and then the correlation of these optical responses to conventional, clinical results to select test wavelengths and a series of constants to form a correlation equation. The correlation equation is then used in conjunction with optical responses at the selected wavelengths taken on an uncharacterized tissue to predict the status of this tissue. However, to obtain good and solid correlations, Rosenthal excises the tissues and obtains in essence a homogeneous sample in which the optical responses do not include the optical signatures of underlying tissues. Rosenthal""s methods, therefore, may not be suitable for in vivo applications.
In studies carried out at the Wellman Laboratories of Photomedicine, using a single fiber depth integrating probe, Schomacker has shown that the auto-fluorescence of the signature of human colon polyps in vivo is an indicator of normality, benign hyperplasia, pre-cancerous, and malignant neoplasia. See Schomacker et al., Lasers Surgery and Medicine, 12, 63-78 (1992), and Gastroenternlogy 102, 1155-1160 (1992). Schomacker further teaches using multi-variant linear regression analysis of the data to distinguish neoplastic from non-neoplastic polyps. However, using Schomacker""s techniques, the observation of mucosal abnormalities was hindered by the signal from the submucosa, since 87% of the fluorescence observed in normal colonic tissue can be attributed to submucosal collagen.
Accordingly, there is a need for a more effective and accurate device to characterize specimens, and particularly in vivo specimens, which will obtain responses from well defined locations or volume elements within said specimen, and present data automatically from a relatively large area comprising a plurality of such locations or volume elements. Furthermore, there is a need for methods to automatically interpret such data in terms of simple diagnostic information on said locations or volume elements.
In U.S. Pat. No. 5,713,364, DeBaryshe et al. teaches the general principles of obtaining valuable analytical data from a volume element in a target sample by using spatial filters with dimensions that are generally larger than the diffraction limits for the wavelengths of the probing radiation. Such spatial filtration is obtained by an optical device including an illumination and a detection system both containing field stops and the field stops being conjugated to each other via the volume element to be analyzed, providing in essence a non imaging volume microprobe.
While the family of devices described in the aforementioned application are very useful in the analysis of a plurality of points within a target sample, there is a need to easily and automatically obtain such data on a full array of points so as to convert these data to an artificial image of the analytical findings over a large area of the sample. This is particularly important when heterogeneous samples, such as biological samples are examined with the non imaging volume microprobe. For instance, when examining tissues to determine the presence or absence of oncological pathologies, or other pathologies, visual techniques are followed, in some cases, by the resection of biopsy specimen. Such techniques are naturally limited in that the physician eye can only assess the visual appearance of potential pathologies, and the number of biopsies taken is by necessity limited. The appearance of pathological tissues does not provide information on the depth of the pathologies, and cannot provide positive diagnosis of the pathology. Furthermore, since biopsies are carried out ex vivo, a time lag between the taking of the biopsy and obtaining its results cannot be avoided. It would be very useful for physicians to have a device capable of performing such diagnostic tasks in vivo and to obtain differential diagnostics (between healthy and pathological tissues) while performing the examination. This is particularly important when performing exploratory surgical procedures, but can be very useful when examining more accessible tissues as well.
A number of devices have been described in the prior art relating particularly to confocal microscopy where illumination and detection arrays are provided. For instance, a confocal scanning microscope in which mechanical scanning of the illuminating and the transmitted (or the reflected) beams is avoided is described in U.S. Pat. No. 5,065,008. A light shutter array is used to provide synchronous detection of a scanned light beam without the need to move a photodetector to follow the scanning beam, and each of the shutters is serving, in essence, as a field stop in the confocal microscope. In other embodiments, two overlapping arrays of liquid crystals are used as optical shutter arrays to attempt reduction in the size of the field stops. As is well known in the art of confocal microscopy, in order to obtain the desired resolution afforded by this technique, the dimensions of the field stops need to be small relative to the diffraction limit of the optical beam used in the system. Other embodiments also provide for two sets of field stops, conjugated within the sample, one set for the illuminating beam and one set for the transmitted or reflected beam. While this patent teaches the use of electronic scanning of the illumination and response beams, the illumination intensity and response signal strength are drastically limited due to the use of dual liquid crystal optical shutters required to achieve the pin-hole effect of a scanning confocal microscope.
Another confocal imaging device is taught in U.S. Pat. No. 5,028,802, where a microlaser array provides a flying spot light source in a confocal configuration. Similarly U.S. Pat. No. 5,239,178 provides for an illuminating grid for essentially the same purpose, except that light emitting diodes are used for the grid""s light sources. These approaches, however, are limited to monochromatic illumination and are usable only with relatively long wavelengths at which solid state laser diodes and thus microlaser arrays or light emitting diode arrays are available.
None of these devices provide for an array of non-imaging volume microprobes. Accordingly, there is a need for a device comprising an array of non-imaging volume microprobes in which a plurality of volume elements in a sample can rapidly be scanned in order to obtain diagnostic or analytical information over a relatively large area of the sample without integrating the data from all the sampled volume elements or locations.
Where a diagnostic device is to come into contact with body tissues, there is a further need that its surfaces be insulated from contact with those tissues in order to avoid contamination. During sterile procedures, the device can introduce contamination into body tissues. Furthermore, the device can become contaminated by contact with the tissues of one patient and transmit that contamination to another patient. While these problems may be avoided by sterilizing the diagnostic device before each use, its delicate optical components may be damaged or incompletely sterilized by available techniques; furthermore, a sterilization cycle prior to each use, even if effective, may be costly and time-consuming.
As an alternative, some form of barrier may be provided that is to be interposed between the diagnostic device and the patient""s tissues. In order to avoid the abovementioned problems of contamination and cross-contamination, however, it is important that a sterile barrier be applied prior to each use of the diagnostic device. Sterility may be effected either by sterilizing the barrier apparatus each time it is used, or by fabricating the barrier apparatus as a single-use device which is sterile and disposable. It is furthermore important with a single-use device that its reuse be prevented so that a fresh sterile insulator is employed for each patient.
It is desirable that an apparatus that provides a barrier insulating the diagnostic device be compatible with the optical characteristics of the diagnostic device, so that the presence of the barrier does not impair the diagnostic device""s accuracy or ease of use. Thus, the method used to isolate the probe from the target tissue must be compatible with the requirement that excitation beams traveling to the tissue and the optical responses therefrom be transmitted through the barrier with minimal optical losses and without signal alteration. When the barrier apparatus is applied to the diagnostic device, it is further important that the optical properties of the system remain stable throughout the diagnostic test, and remain consistent from one test to another. To ensure these qualities, it is desirable that the barrier be tightly adherent to the probe during a diagnostic procedure. Tight adherence of the barrier to the probe will furthermore avoid accidental detachment between the probe and the sheath during the procedure, thus preventing this mechanism of contamination.
It would be further desirable to provide a barrier apparatus that conforms to the anatomic area in which it is being used. For example, a differently shaped barrier apparatus may be required for diagnosing tissues through an endoscope than would be useful for diagnosing abnormalities of the cervix. One device adapted for the examination of the cervix uteri may be termed a colpoprobe. A barrier apparatus shaped to fit over a colpoprobe might have particular anatomic and optical characteristics. It would be advantageous, for example, during a colposcopic examination to provide not only an image of the cervix, but also a set of data correlated with important tissue variations from the normal state which cannot be visualized in normal imaging systems. It is desirable that, since the contemplated use of certain diagnostic systems such as the colpoprobe includes screening of large populations, it is important that the systems and their biological isolation sheaths be easy to use in an error-free manner, and that the sheath be readily attached and detached from the diagnostic system rapidly, simply and without mistake. A barrier insulating the colpoprobe from the tissues of the vagina and the cervix would advantageously be compatible with both imaging and non-imaging applications.
The prior art teaches the uses of an external barrier or sheath as an alternative to the complete sterilization of a diagnostic or therapeutic device. For instance, sanitary covers or speculate for tympanic thermometers probes are described in three US patents issued to O""Hara et al., U.S. Pat. Nos. 4,662,360, 5,516,010 and 5,707,343. However, the covers disclosed in these patents only fit tympanic thermometers and cover only the tip of the device, not permitting modification. Furthermore, nothing in the design of these tympanic thermometers covers prevents their repeated use.
As another example, Furukawa et al., in U.S. Pat. Nos. 5,730,701 and 5,860,913, and Katsurada et al., U.S. Pat. No. 5,865,726, teach the use of disposable tips for side view type endoscope. However, these tips do not provide biological isolation for anything beyond the tip. Furukawa et al. in U.S. Pat. No. 5,730,701 suggest that the attachment means or locks plastically deform upon detachment, thus preventing the reuse of the same tip cover. However, these locking mechanisms merely deform, rather then break away. Thus reshaping a used disposable tip to the original shape by manipulation of the locking mechanism is feasible, permitting the tip""s reuse. Furthermore, this feature requires that the first attempt in affixing the tip to an endoscope""s end be successful; otherwise, the tip cannot be used and will need to be discarded.
Yabe et al., in a number of U.S. Pat. Nos. 5,419,311, 5,458,132, 5,458,133, 5,536,236, 5,545,121 and 5,556,367, describe a variety of endoscope covers that engulf the whole endoscope. However, these devices are specific to the particular device, an endoscope with a set of complex features. The covers themselves are complicated devices, difficult to assemble over an endoscope and requiring specialized training, making their use impractical for a screening setting. Furthermore, these covers include channels for fluids and for air insufflation and are specifically designed each to fit a specific endoscope design and specific endoscope functionality. As an example, U.S. Pat. No. 5,536,236 discloses an endoscope cover bearing optical filters preventing back scattering from laser beams used in endoscopic procedures through said endoscope. The endoscope cover of the ""236 Patent is further characterized by an inner surface designed to hold it in place over the endoscope by friction fitting. As another example, U.S. Pat. No. 5,545,121, teaches display means that indicate that the cover has been properly applied to the specific endoscope for which it is used. U.S. Pat. No. 5,556,367 discloses the additional feature of adjustable length, whereby the cover may be lengthened to fit any of a preselected series of endoscopes. As previously mentioned, each of these covers is intended for a use with a particular endoscope system. Further, none of these provides a biological barrier that may be fitted on a simple optical diagnostic device with great ease by operators with little training. Nor do these covers provide means that assure that the same barrier or sheath is not used sequentially on different patients.
Chikama in U.S. Pat. Nos. 5,154,166 and 5,159,919 discloses an endoscope cover made of a rigid material that has a complex structure including a mating longitudinal groove in the endoscope anchoring an opposing anchoring projection in the rigid endoscope cover. This cover has the same shortcomings cited above for the various endoscope covers taught by Yabe et al.
Kimura et al. in U.S. Pat. No. 5,695,448 disclose a simple tubular disposable sheath having at least a distal transparent end for viewing and special positioning means assuring that the distal transparent end is within the view range of the endoscope. This cover, like many of those mentioned above, does not have means for preventing reuse. Furthermore, no special means are disclosed whereby the transparent window may transmit not only images of the target operational area but also accurate optical responses from target tissues subjected to excitation beams for diagnostic purposes.
Williams et al. in U.S. Pat. Nos. 4,237,984 and 5,413,092 describe a sheath-like cover for an endoscope bearing a very thin lens cover (between 0.002xe2x80x3 to 0.010xe2x80x3 thick) intended as an improvement over thicker lens covers for reducing back reflections of light from the illumination channel into the field of view of the endoscope. This feature is not adapted for UV-induced fluorescence systems like those contemplated herein because in these systems the excitation beam uses wavelengths that differ markedly from the wavelengths obtained as responses from the excited tissue, and minor reflections of the excitation beams are of little importance.
Saab in U.S. Pat. No. 5,37,734 and Hamlin et al. in U.S. Pat. No. 5,690,605 disclose rigid tubular structures as disposable endoscopic sheaths of a configuration inapplicable to the devices of the present invention. Further, neither patent teaches methods for preventing reuse.
Another type of a disposable endoscope cover is taught by Sidall et al. (U.S. Pat. No. 4,741,326), which describes a sheath that is manually rolled over the endoscope. The sheath has a complex structure comprising its distal element. Employing this device is complicated, so it has not been widely adopted. Furthermore, the complex distal end has tubular structures attached thereto that are not suitable for probes such as those disclosed herein.
Oneda et al. in U.S. Pat. No. 4,979,498 describe a disposable light transmitting sleeve disposed about the distal member of a cervicoscope. This device, however, fails to provide for means that prevent the reuse of the sleeve, nor does it provide the special distal end properties required to optimize the transmission of the excitation beams to the tissues and reception by the system of optical responses from said tissues.
Sinofsky in U.S. Pat. No. 5,773,835 proposes the use of a casing made of a. fluoropolymer, acting as a disposable sheath over a thin UV illuminator/collector assembly that could be used in fluorescence analysis of tissue within body cavities. Using such a material for a sheath may be particularly beneficial when the optical head provides for diagnostic information by excitation of target tissue with a UV beam and detection of the fluorescence response from the tissue, because fluoropolymers have only minimal autofluorescence. However, the Sinofsky sheath provides no means that assure that it will not be reused on multiple subjects. Nor does the Sinofsky sheath provide an optical window adapted for a plurality of optical functions, as may be required by an optical probe according to the systems and methods of the present invention.
Similarly, Sklandev et al. in U.S. Pat. No. 5,855,551 describe a disposable sheath intended to be used with a probe that uses both optical and electrical responses from body tissues for diagnostic purposes. In this device, however, the disposable sheath itself contains active elements of the diagnostic system such as light emitting diodes and electrical contacts. Furthermore, this patent teaches no means for preventing reuse of the disposable sheath on subsequent patients.
There is therefore a need in the art to provide for a disposable biological barrier or sheath compatible with the particular characteristics of a non-imaging volume microprobe. There is a need for a sheath that minimizes the fluorescence response directly from the optical window thereof In addition, it would be advantageous to have a sheath adapted for the anatomic area where the non-imaging volume microprobe would be used. Furthermore, there is a need for such a sheath constructed to prevent its reuse. Finally, there is a need to devise a sheath that is of simple structure, easy to mount and to remove from the diagnostic instrument.
In one embodiment, the present invention may automatically obtain optical responses from a three dimensional array of volume elements or locations by providing a plurality of non imaging volume microprobes in parallel which automatically presents mapping of the diagnostic information sought, in a plane generally parallel to the surface of the specimen (the xy plane) and in the z direction which is generally perpendicular to the xy plane. As used in this specification, the term xe2x80x9clocationxe2x80x9d refers to any point in three dimensional space related to the tissue sample. A location may be a point within the substance of a tissue sample, or it may be found on the surface of the tissue sample. A location within a tissue sample may be termed a volume element. In some embodiments, the systems and methods of the present invention may be used for the evaluation of any material. To evaluate a material, these systems and methods may determine a characteristic of the material. In certain embodiments, the systems and methods of the present invention are directed to a sample of a biological material. A biological material is understood to include those materials derived from or related to unicellular or multicellular biological organisms. A sample of a biological material may include one or more than one specimens of the biological material under investigation. The sample of biological material may be located in an in vivo system or in an in vitro system. If in vivo, the sample may be adjacent to other tissues of like or different kinds. The sample may represent an area of abnormality within a tissue, or the sample may represent an entire tissue. The tissues comprising an in vivo system may be surrounded by other adjacent tissues. The systems and methods of the present invention may be used within a living organism to examine a body tissue in vivo. A body tissue may reside or be derived from a human or a non-human living organism. Other uses for these systems and methods will be apparent to ordinary practitioners of the relevant arts. For the purposes of this specification, the term xe2x80x9cpatientxe2x80x9d refers to anyone undergoing diagnostic evaluation using certain of the systems and methods disclosed herein.
In one embodiment of these disclosed systems and methods, optical responses from an array of volume elements are further analyzed to provide visually (namely on a monitor) information which is not readily available by direct examination of the sample. This is achieved by, in essence, providing an artificial three dimensional biochemical map composed from the optical responses, or more accurately, derivatives of such responses, of each individual volume element examined in an array, and by further converting these biochemical data to an artificial pathological image delineating the nature, extent and depth of pathologies observed. This is achieved by creating an artificial pathological scale, for each pathology of interest, by training the instrument to recognize specific pathologies. In one embodiment, a training set of specimens on which optical responses with a non imaging volume microprobe were collected, is subjected to a rigorous laboratory determination of the pathological state of each of its specimens and a value is assigned to each specimen on the artificial pathological scale. A set of linear equations relating to the responses (or functions of the responses) for each specimen to the pathological states, is constructed and optimized solutions for the correlation coefficients sought. These correlation coefficients are then used to transform responses obtained on unknown specimen to obtain the pathological state of these unknown specimen.
The objectives of the instant invention are achieved by providing an array of optical assemblies each consisting of two conjugated, or partially conjugated, optical assemblies. In each such assembly, the first optical assembly is designed to image selectively a transmitted beam from a light source, or another source of radiation, within a plurality of selected volume elements of a sample in a sequential manner. The second optical assembly is designed to collect light, or radiation emanating from the volume elements, in the same sequential manner, and transmit the collected light or radiation to a detector for further analysis of the interaction of the first transmitted beam with the volume elements. The first optical assembly includes a first field stop to achieve selective illumination of a selected volume element, and the second optical assembly includes a second field stop to restrict acceptance of said emanating radiation or light into the collection optics, essentially only from the selected volume element. Furthermore, a controller is provided to adjust the depth of the selected volume elements relative to the surface of the sample by controlling the respective focal points of the two optical assemblies while keeping them conjugated and having the volume element as a common conjugation point for both optical assemblies.
Sequential illumination of the various volume elements in an array is desired to assure that only responses from a given volume element are collected by the optical assembly associated with the volume element at any given time.
The sequential illumination of a plurality of volume elements may be carried out with a variety of devices. In some embodiments of the invention, an array of optical shutters is interposed between the light source and the sample, each shutter serving as either a field stop or an aperture stop for a specific optical assembly. In some embodiments, a single array of optical shutters is provided, while in other embodiments two arrays of optical shutters are provided. In yet another embodiment of the invention, an array of micromirrors is used to control the sequential illumination and response collection of the various volume elements in the sample. In yet another embodiment of the invention, an arrayed bundle of optical fibers is used to sequentially illuminate an array of volume elements in the sample and to collect sequentially responses from the volume elements. Appropriate movement of the optics so as to probe various depths of the sample is provided.
The optical responses from the selected volume elements bear important information about the volume elements, such as chemistry, morphology, and in general the physiological nature of the volume elements. When the sample is spectrally simple, these optical responses are analyzed by classical spectral techniques of peak matching, deconvolution or intensity determination at selected wavelengths. One such system may be the determination of the degree of homogeneity of a mixture or a solution of a plurality of compounds. However, when the samples are complex biological specimens, as mentioned above, the spectral complexity is often too great to obtain meaningful diagnosis. When such biological specimens are analyzed for subtle characteristics, we surprisingly found that the application of correlation transforms to spatially filtered optical responses obtained from an array of discrete volume elements, or the use of such transforms in conjunction with data obtained through non imaging microscopy, yields diagnostically meaningful results.
Specifically, we first select a training sample of a specific target pathology. Such a sample will preferably have at least 10 specimens. Optical responses are first collected from well defined volume elements in the specimens and recorded. These optical responses may be taken with an array microprobe or with a single volume microprobe device as described in the aforementioned co-pending application. The same volume elements that have been sampled with the non imaging volume microprobe are excised and biopsies (namely cytological analysis of the excised volume elements) is carried out in a classical pathological laboratory and the specimens are scored on an arbitrary scale which relates to the extent of the pathology, C (for instance a specific cancer) being characterized. These scores, Cj, where Cj is the score value assigned to the specimen j within the training set, should be as accurate as possible, and thus an average of a number of pathologists"" scores (determined on the same volume elements, j), may be used. We now create a set of equations Gaic F(Iij)=Cj, where i designates a relatively narrow spectral window (usually between 5 and 50 nm) and thus F(Iij) is a specific function of the response intensity or other characteristics of the spectral response in the window i for volume element j. The function F is sometimes the response intensity itself, in that window, namely, F(Iij)=Iij, or F(Iij)=(dIij/dxcex), where xcex is the median wavelength in the window i. The factors aic, the correlation transform""s coefficients for the pathology C, are now found from the set of equations created above, by means well known in the prior art, such as multivariate linear regression analysis or univariant linear regression analysis. In such analysis, the number of wavelength windows i required to obtain faithful correlations between the optical responses and the pathological derivations of the values Cj, is minimized and the set of correlation coefficients aic for the pathology, C are found. When we now record the responses (Iik) (which is a vector in the space of i optical windows, now minimized to a limited number of discrete elements) on a sample outside the training set and apply the transform operator (aic) on the vector F(Iik), namely obtain the sum Eaic F(Iik)=Ck, we automatically obtain the score for the target pathology C for the volume element sampled.
It should be understood that other statistical tools, such as principal component regression analysis of the optical responses, may be used as well. In addition, linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), or their weighted average i.e. regularized discriminant analysis (RDA) can be used. One may also consider using in the correlation transforms, in lieu of functions of the optical responses at specific wavelengths, the Fourier transform of the total spectral responses. Furthermore, while taking the spectral responses from specific volume elements, these responses may be treated optically through either a spatial Fourier transform generator (such as a Sagnac interferometer) or a temporal Fourier transform generator (such as a Michelson interferometer), and then the data obtained may be used to create the desired correlation matrices to train the system for further data acquisition and image generation of the distribution of possible pathologies.
Instruments embodying the invention are deemed useful for obtaining artificial images of some characteristics of turbid materials, such as biological tissue, plastics, coatings, and chemical reaction processes, and may offer particular benefits in analysis of biological tissue, both in vitro and in vivo. To provide analysis of biological materials located within a living body, certain embodiments of the present invention may be adapted to work with existing endoscopes, laparoscopes, or arthroscopes. The systems and methods of the present invention may be adapted to work within a body orifice, such as the mouth, the ear canal, or the vagina. The systems and methods of the present invention may be adapted to work within a body lumen, such as the colon or the bladder. The systems and methods of the present invention may be adapted to work within a body cavity such as the peritoneal or the pleural cavity. Other adaptations may be envisioned by ordinary skilled artisans in the field.
To adapt the invention for diagnostic purposes involving contact with biological tissues, the diagnostic apparatus may be provided with a covering to insulate it from contact with biological tissues. It is an objective of the present invention to provide a protective sheath for in vivo optical diagnostic systems that may serve as a biological barrier between patient""s tissue and the optical probe. In one embodiment, the systems and methods of the invention may provide a barrier disposed external to the diagnostic probe that separates the probe from any tissue of the body, including those tissues in continuity with the target tissue sample and including those tissues adjacent to or in proximity to the tissue sample. A barrier according to these systems and methods may insulate a colposcopic probe, for example, from contact with the tissues of the cervix, vagina and vulva. Other barriers may be envisioned by practitioners skilled in the relevant arts that will prevent the probe from contact with relevant body tissues. It is a further objective in certain embodiments that the biological barrier be disposable and adapted for a single use. The term xe2x80x9csingle usexe2x80x9d is understood to comprise the use for a single diagnostic measurement performed by the probe. It is desirable that the barrier or disposable sheath be capable of use with only one patient. As used in only one patient, a unique individual, the biological barrier may be adapted for a single use or may be adapted for multiple uses. Systems according to the present invention are adapted to prevent the use of the probe in more than one patient.
It is yet another objective to provide a sheath constructed to conform to the optical requirements of the diagnostic systems and methods of the present invention. In one embodiment, such a sheath advantageously would provide minimal interference with the optical responses produced by tissues after their excitation by a beam of electromagnetic radiation produced by a diagnostic system according to the present invention. In one embodiment, such a sheath would include an optical window, an optical filter, a lens or a polarizer capable of being exposed to ultraviolet radiation without producing a significant fluorescent response.
It is yet another objective to provide a protective sheath for a colposcopic optical probe or an optical probe adapted for the examination of the cervix uteri.
It is yet another object of the present invention to provide a sheath which may be mounted and dismounted on the optical probe with great ease and minimal training. It is an object of the invention that a sheath be equipped with an affixation mechanism that also orients the sheath on the probe in a preselected, optimal direction. It is a further object of the invention that a sheath possess mechanisms that facilitate the assurance of single use for the sheath. In one embodiment, a sheath may be provided with a mechanical affixation mechanism that is suitable only for a single use. In one embodiment, the affixation mechanism may entail damage to the attachment apparatus when the sheath is detached from the probe. In another embodiment, the sheath may be provided with an identifying marker that may be read by the probe so that the system may determine that the sheath is suitable for use. An identifying marker may provide data about the unused state of the sheath or data about the previous use of the sheath. It is an object of the present invention that the sheath interact with the probe to prevent the use of the probe in the absence of an unused sheath. A probe being used with the barrier may comprise a processing system that correlates certain data borne by the identifying marker on the sheath with an indicator that indicates or relates to an unused or a previously used state of the sheath. The probe to be used with the barrier may include a receptor system that receives a signal generated by a sensor on the barrier and that thereupon renders the probe operable or inoperable, depending upon the type of signal received. A probe rendered capable of being used may be termed operable or activated. In one embodiment, the probe may be inoperable in the absence of an unused sheath. In another embodiment, an unused sheath may be required for a signal to be produced that activates the probe. In one embodiment, the invention may provide a system for controlling use of a diagnostic apparatus that includes a diagnostic apparatus, a disposable sheath with an identifier that bears unique data to characterize that particular disposable sheath, a detector that produces a signal indicative of the unique data borne by the identifier, and a receiver system that responds to the signal produced by the detector, that determines the state of the disposable sheath and that provides a second signal that regulates activation of the probe. As understood herein, a signal or any other mechanism that regulates activation of the probe may activate the probe, may prevent it from being activated, or may provide any other type of regulation that affects the use of the probe.
It is an object of the invention that these systems and methods include a plurality of interactions between sheath and probe whereby the integrity of the sheath and its proper use are assured. In one embodiment, these systems and methods may comprise a database with which the probe apparatus communicates to determine the unused state of the sheath. In another embodiment, these systems and methods may comprise a set of diagnostic tests that ensure the integrity of the sheath and its proper positioning upon the probe, or that ensure the proper positioning of the probe with respect to the patient, or that ensure the proper type of sheath be placed on the probe. It is an object of the invention to provide proper sheaths for a plurality of anatomic areas where the probe may be used, for example the cervix and the endocervix.